Triazolopyridyl compounds as aldosterone synthase inhibitors

ABSTRACT

This invention relates to triazolopyridyl compounds of the structural formula: 
     
       
         
         
             
             
         
       
     
     or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.

RELATED APPLICATIONS

This application claims benefit to provisional application U.S. Ser. No.61/537,923, filed on 22 Sep. 2011, herein incorporated by reference

FIELD OF THE INVENTION

The present invention relates to triazolopyridyl compounds, whichselectively inhibit aldosterone synthase (CYP11B2) with diminishedinhibition or affect on steroid-11-β-hydroxylase (CYP11B1) inhibitors.The inventive compounds potentially have utility in treatingcardiovascular diseases, such as hypertension or heart failure. Thepresent invention also relates to pharmaceutical compositions comprisingthe inventive compounds as well as processes for their preparation.

BACKGROUND OF THE INVENTION

Aldosterone is a steroid hormone secreted in the adrenal cortex. Inprimary cells of the distal tubules and collecting ducts of the kidney,aldosterone binding to the mineralocorticoid receptor (MR) results inthe retention of sodium and water and excretion of potassium, which inturn leads to increased blood pressure. Aldosterone also causesinflammation that leads to fibrosis and remodeling in the heart,vasculature and kidney. This inflammation may proceed by MR-dependent aswell as MR-independent mechanisms (Gilbert, K. C. et al., Curr. Opin.Endocrinol. Diabetes Obes., vol. 17, 2010, pp. 199-204).

Mineralocorticoid receptor antagonists (MRAs), such as spironolactoneand eplerenone, have been used previously to block the effects ofaldosterone binding to MR. When given in addition to standard therapiessuch as angiotensin-converting enzyme (ACE) inhibitors and loopdiuretics, the nonselective MRA spironolactone and the selective MRAeplerenone significantly reduced morbidity and mortality in patientswith heart failure or myocardial infarction (Pitt, B. et al., New Engl.J. Med., vol. 341, 1999, pp. 709-717; Pitt, B. et al., New Engl. J.Med., vol. 348, 2003, pp. 1382-1390). However, the nonselective MRAspironolactone can also bind to and act at other steroid receptors, andas a consequence its use is associated with sexual side effects such asgynecomastia, dysmenorrhoea and impotence (Pitt, B. et al., New Engl. J.Med., vol. 341, 1999, pp. 709-717; MacFadyen, R. J. et al., Cardiovasc.Res., vol. 35, 1997, pp 30-34; Soberman, J. E. et al., Curr. Hypertens.Rep., vol. 2, 2000, pp 451-456). Additionally, both spironolactone andeplerenone are known to cause elevated plasma potassium levels(hyperkalemia) and elevated aldosterone levels.

An alternative method of blocking the effects of aldosterone is toinhibit its biosynthesis. CYP11B2 is a mitochondrial cytochrome P450enzyme that catalyzes the final oxidative steps in the conversion of11-deoxycorticosterone, a steroidal precursor, to aldosterone (Kawamoto,T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992, pp. 1458-1462).Compounds that inhibit CYP11B2 should thus inhibit the formation ofaldosterone. Such compounds, particularly those of nonsteroidalstructure, should provide the beneficial effects of MRAs, without theadverse effects derived from steroid receptor binding or MR-independentinflammatory pathways. The art has recognized that reducing aldosteronelevels by inhibiting aldosterone synthase could represent a newpharmaceutical strategy that has the potential to treat a disorder ordisease characterized by increased stress hormone levels and/ordecreased androgen hormone levels in a patient (WO2011/088188 toNovartis). Compounds possessing this activity might be expected to treatdisease states such as heart failure, cachexia, acute coronary syndrome,Cushing's syndrome or metabolic syndrome.

CYP11B1 is a related enzyme that catalyzes the formation ofglucocorticoids, such as cortisol, an important regulator of glucosemetabolism. Because human CYP11B2 and CYP11B1 are greater than 93%homologous, it is possible for nonselective compounds to inhibit bothenzymes (Kawamoto, T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992,pp 1458-1462; Taymans, S. E. et al., J. Clin. Endocrinol. Metab., vol.83, 1998, pp 1033-1036). It would be preferable, however, fortherapeutic agents to selectively inhibit CYP11B2 and the formation ofaldosterone with diminished inhibition of, or affect on, CYP11B1 and theproduction of cortisol.

WO 2009/135651 to Elexopharm describes6-pyridin-3yl-3,4,-dihydro-1H-quinolin-2-one derivatives as beingCYP11B2 inhibitors. Two compounds described therein are lactamderivatives of the formula:

Structurally similar lactam and thiolactam compounds are disclosed byLucas et al., J. Med. Chem. 2008, 51, 8077-8087; those compounds aresaid to be potential inhibitors of CYP11B2. Lucas et al. in J. Med.Chem. 2011, 54, 2307-2309 describes certain pyridine substituted3,4-dihydro-1H-quinolin-2-ones as being highly potent as selectiveinhibitors of CYP11B2. An abstract of a dissertation reports that aseries of novel heterocyclic-substituted4,5-dihydro-[1,2,4]triazolo[4,3a]quinolones was evaluated for itsaldosterone synthase activity; one of the compounds is reported asexhibiting excellent selectivity of CYP11B2 over CYP11B1.

Benzimidazole derivatives are also known in the art to treat variousdisease states. For example, U.S. Pat. No. 6,897,208 to AventisPharmaceuticals describes compounds of the formula:

wherein R¹ is an optionally substituted aryl or heteroaryl group and A₅is H or alkyl. These compounds are said to be kinase inhibitors. Otherbenzimidazoles derivatives are known in the art. For example, WO2012/012478 to Merck describes benzimidazole analogues as having theability to CYP11B2. WO2002/46168 A1 to AstraZeneca describesbenzimidazoles derivatives that are useful in the treatment orprophylaxis of Alzheimer's disease, anxiety disorders, depressivedisorders, osteoporosis, cardiovascular disease, rheumatoid arthritis orprostate cancer. US2007/0270420 A1 to Vertex Pharmaceuticals describesbenzimidazole compounds that are useful of inhibitors of GSK-3 and Lckprotein kineases. Other benzimidazole derivatives are described in US2009/0018124 A1, WO2004/082638 A1, WO2008/073451 A1 and US 2005/0272756A1.

Novartis in US 2010/0261698 A1 describes indole derivatives of theformula:

Novartis indicates that these compounds inhibit aldosterone synthase andmay be useful in the treatment of disease states such as heart failureand hypertension. In WO2010/130,796 A1 and WO2011/061168, Novartisdiscloses aryl-pyridine derivatives that are said to inhibit aldosteronesynthase.

US 2009/0221591 A1 to Universitat des Saarlandes also disclosescompounds that inhibit CYP11B1 and CYP11B2. WO 2009/135651 toUniversitat des Saarlandes teaches that compounds of the formula:

possess the ability to inhibit aldosterone synthase.

WO 1999/400094 Bayer AG discloses oxazolidinones with azol-containingtricycles as having antibacterial activity.

U.S. Pat. No. 7,381,825 to Takeda describes histone deacetylaseinhibitors of the formula

Z-Q-L-M

where Q is a substituted or unsubstituted aromatic ring, L is asubstituent providing between 0-10 atoms separation between M and theremainder of the compound, M is a substituent capable of complexing witha deacetylase catalytic site and/or metal ion, and Z is list of bicyclicgroups, including, but not limited to:

where X is CR₁₂ or N. These compounds are said to be useful in treatingcell-proliferative diseases such as, for example, leukemia, melanoma,bladder cancer, etc.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides for a noveltriazolopyridyl compounds, which are inhibitors of CYP11B2, ormetabolites, stereoisomers, salts, solvates or polymorphs thereof,processes of preparing such compounds, pharmaceutical compositionscomprising one or more such compounds, processes of preparingpharmaceutical compositions comprising one or more such compounds andpotentially methods of treatment, inhibition or amelioration of one ormore disease states associated with inhibiting CYP11B2 by administeringan effective amount at least one of the inventive triazolopyridylcompounds to a patient in need thereof.

In one aspect, the present application discloses a compound or apharmaceutically acceptable salt, metabolite, solvate, prodrug orpolymorph of said compound, said compound having the general structureshown in Formula I:

wherein:

Ring A is attached to Ring B via positions D and E and is:

D is C;

E is N;

R¹ is H or alkyl;

R² is halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷,—C(O)N(R¹¹)(R¹²); —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷;alkyl optionally substituted one or more times (e.g., 1 to 4 times) byhalogen, —OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;or heteroaryl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷;

R⁴ is H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)R⁷; —C(O)N(R⁸)(R⁹),—C(O)R⁷; —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—R⁷; alkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)S(O)₂—R⁷, or —S(O)_(n)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;or heteroaryl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷;

R⁵ is H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R′)C(O)R⁷; —C(O)N(R⁸R⁹);—C(O)R⁷; —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—R⁷; alkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)S(O)₂—R⁷, or —S(O)_(n)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R or —S(O)_(m)—R⁶; aryl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R or —S(O)_(m)—R⁷;or heteroaryl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷;

-   -   or R⁴ and R⁵ are joined together to form a 5-7 membered        carbocyclic or heterocyclic ring that is fused to the pyridyl        ring to which R⁴ and R⁵ are attached, wherein the ring formed by        R⁴ and R⁵ is optionally substituted by 1 to 3 R⁶;

R⁶ is independently H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹)C(O)R⁷;—C(O)N(R⁷)(R⁸); —C(O)N(R⁸)(R⁹); —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)SO₂—R⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times (e.g., 1 to4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁸—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;or heteroaryl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷;

R⁷ is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰or —S(O)_(m)—R¹⁰; aryl optionally substituted one or more times (e.g., 1to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR¹⁰,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰;or heteroaryl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN,—N(R⁹)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰;

R⁸ is independently H or alkyl;

R⁹ is independently H or alkyl;

-   -   or R⁸ and R⁹ are joined together with the nitrogen to which they        are attached form a saturated 5- to 7-membered heterocyclic        ring;

R¹⁰ is independently H or alkyl;

R¹¹ is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰or —S(O)_(m)—R¹⁰; aryl optionally substituted one or more times (e.g., 1to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷;

R¹² is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰or —S(O)_(m)—R¹⁰; aryl optionally substituted one or more times (e.g., 1to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷;

a is 0, 1, 2, 3 or 4 (e.g., 0, 1 or 2);

n is 1 or 2; and

m is 0, 1 or 2.

Another aspect of the present invention is pharmaceutical compositionscomprising a therapeutically effective amount of at least one compoundof Formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

Another aspect of the present invention is pharmaceutical compositionscomprising a therapeutically effective amount of at least one compoundof Formula I or a pharmaceutically acceptable salt thereof, atherapeutically effective amount of at least one additional therapeuticagent and a pharmaceutically acceptable carrier.

Another aspect of the present invention is the prevention of one or morediseases states associated with inhibiting CYP11B2 by administering aneffective amount of at least one of the inventive triazolopyridylcompounds to a patient in need thereof.

It is further contemplated that the combination of the invention couldbe provided as a kit comprising in a single package at least onecompound of Formula I or a pharmaceutically acceptable salt thereof in apharmaceutical composition, and at least one separate pharmaceuticalcomposition, such as, for example a separate pharmaceutical compositioncomprising a therapeutic agent.

The compounds of the present invention could be useful in the treatment,amelioration or prevention of one or more conditions associated withinhibiting CYP11B2 by administering a therapeutically effective amountof at least one compound of Formula I or a pharmaceutically acceptablesalt thereof to a mammal in need of such treatment. Conditions thatcould be treated or prevented by inhibiting CYP11B2 includehypertension, heart failure such as congestive heart failure, diastolicdysfunction, left ventricular diastolic dysfunction, heart failure(including congestive heart failure), diastolic dysfunction, leftventricular diastolic dysfunction, diastolic heart failure, systolicdysfunction, hypokalemia, renal failure (including chronic renalfailure), restenosis, syndrome X, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,vascular diseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, ischemia, myocardial andvascular fibrosis, myocardial necrotic lesions, vascular damage,myocardial necrotic lesions, myocardial infarction, left ventricularhypertrophy, cardiac lesions, vascular wall hypertrophy, endothelialthickening or fibrinoid necrosis of coronary arteries.

The compounds of the present invention also might be useful in treatingone or more conditions characterized by increased stress hormone levelsand/or decreased androgen hormone levels in a mammal by administering atherapeutically effective amount of at least one compound of Formula Ior a pharmaceutically acceptable salt thereof to a mammal in need ofsuch treatment. Conditions characterized by increased stress hormonelevels and/or decreased androgen hormone levels in a mammal include, forexample, heart failure (e.g., acute heart failure, acute decompensatedheart failure, chronic heart failure, chronic heart failure withimpaired exercise tolerance or chromic heart failure with muscleweakness), cachexia (e.g., cardiac cachexia, COPD-induced cachexia,cirrhosis-induced cachexia, tumor-induced cachexia or viral(HIV)-induced cachexia), acute coronary syndrome, Cushing's syndrome ormetabolic syndrome.

Another aspect of the present invention could be the use of a compoundof Formula I or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment, amelioration orprevention of one or more conditions associated with inhibiting CYP11B2in a patient.

This invention further relates to a process for the preparation of thecompounds of Formula I or their pharmaceutically acceptable salts.Moreover, this invention also relates to the use of the compounds ofFormula I or their pharmaceutically acceptable salts to validate invitro assays, such as, for example the V79-Human-CYP11B2 andV79-Human-CYP11B1 discussed later in the application.

These and other objectives will be evident from the description of theinvention contained herein.

DETAILED DESCRIPTION

In an embodiment, the present invention provides compounds representedby structural Formula I or pharmaceutically acceptable salt thereof,wherein the various moieties are as described as above.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula II

wherein R², R⁴, R⁵ and a are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula III

wherein R¹, R², R⁴, R⁵ and a are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula IV

wherein R², R⁶ and a are as defined in Formula I and b is 0, 1 or 2(e.g, where b is 0, or where b is 1 and R⁶ is alkyl or halo).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula V

wherein R¹, R², R⁶ and a are as defined in Formula I and b is 0, 1 or 2(e.g, where b is 0, or where b is 1 and R⁶ is alkyl or halo).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V, where a is 0 or a is 1 or 2 and R² is independently halogen(e.g., F or Cl), —CN, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl), OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butylor tert-butyl) or haloalkyl (e.g., —CF₃)), haloalkyl (e.g., —CF₃),cycloalkyl (e.g., cyclopropyl or cyclohexyl) or phenyl optionallysubstituted by halogen.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI or II wherein a is 1 or 2 and R² is independently halogen (e.g., —F,—Cl or —Br) or alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁴ is H, halogen (e.g., —F or —Cl), —CN, alkyl(e.g., methyl or ethyl) haloalkyl (e.g., —CF₃) or cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁴ is H, halogen (e.g., —F or —Cl), —CN, alkyl(e.g., methyl or ethyl) or cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁴ is H or alkyl (e.g., methyl or ethyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁵ is H, halogen (e.g., —F or —Cl), —CN, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl), —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) or haloalkyl(e.g., —CF₃)), haloalkyl (e.g., —CF₃) or phenyl optionally substitutedby halogen, —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) or haloalkyl(e.g., —CF₃)), haloalkyl (e.g., —CF₃) or cycloalkyl (e.g., cyclopropyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁵ is H, halogen (e.g., —F or —Cl), —CN, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl), —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) or haloalkyl(e.g., —CF₃)), haloalkyl (e.g., —CF₃) or phenyl optionally substitutedby halogen, —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) or haloalkyl(e.g., —CF₃)) or haloalkyl (e.g., —CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through III described above where R⁴ is H and R⁵ is H, halogen(e.g., —F or —Cl), —CN, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl), —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butylor tert-butyl) or haloalkyl (e.g., —CF₃)), haloalkyl (e.g., —CF₃) orphenyl optionally substituted by halogen, —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butylor tert-butyl) or haloalkyl (e.g., —CF₃)), or haloalkyl (e.g., —CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through III described above where R⁴ is H, alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl) or cycloalkyl (e.g., cyclopropyl) and R⁵ is H, halogen(e.g., —F or —Cl), alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl) or cycloalkyl (e.g.,cyclopropyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormulae I through III described above where R⁵ is —C(O)OR⁷ (e.g., R⁷ isC₁-C₄-alkyl or phenyl, optionally substituted by halogen or haloalkyl).

Another embodiment of the present inventions is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through III described above or their pharmaceuticallyacceptable salts thereof where R⁴ is H and R⁵ is a group of the formula:

-   -   where:        -   R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with            1 to 3 —F (e.g. —CF₃);        -   R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with            1 to 3 —F (e.g. —CF₃);            -   R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3                —F (e.g. —CF₃), is —OC₁—C₃-alkyl,                —N(H)S(O)₂—C₁-C₃-alkyl, optionally substituted with 1 to                3 —F (e.g. —CF₃), —N(H)C(O)C₁-C₃-alkyl, optionally                substituted with 1 to 3 —F (e.g. —CF₃).

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Mammal” means humans and other mammalian animals.

The following definitions apply regardless of whether a term is used byitself or in combination with other terms, unless otherwise indicated.Therefore, the definition of “alkyl” applies to “alkyl” as well as the“alkyl” portions of “hydroxyalkyl”, “haloalkyl”, “alkoxy”, etc.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched.

“Halo” refers to fluorine, chlorine, bromine or iodine radicals.Examples are fluoro, chloro or bromo.

“Halogen” means fluorine, chlorine, bromine, or iodine.

“Haloalkyl” means a halo-alkyl- group in which the alkyl group is aspreviously described. The bond to the parent moiety is through thealkyl. Non-limiting examples of suitable haloalkyl groups includefluoromethyl, difluoromethyl, —CH₂CF₃, —CH₂CHF₂—CH₂CH₂F, or an alkylgroup with one or more terminal carbons tri-substituted with a halogen(e.g., —F) such as, for example trifluoromethyl, —C₁-C₃alkyl-CF₃,—CH(CH₃)(CF₃), —CH(CF₃)₂ and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of suitable multicycliccycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, aswell as partially saturated species such as, for example, indanyl,tetrahydronaphthyl and the like.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. Non-limiting examples of suitable aryl groups includephenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

“Heterocycloalkyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocycloalkyl root name means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocycloalkyl ring may exist protected suchas, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like;such protections are also considered part of this invention. Thenitrogen or sulfur atom of the heterocycloalkyl ring can be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Non-limiting examples of suitable monocyclic heterocycloalkyl ringsinclude piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiopyranyl, oxetanyl,tetrahydrothiophenyl, lactam, lactone, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination, provided that the rings do not include adjacent oxygenand/or sulfur atoms. N-oxides of the ring nitrogens are also included,as well as compounds wherein a ring nitrogen is substituted by an alkylgroup to form a quaternary amine. Preferred heteroaryls contain about 5to about 6 ring atoms. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl,tetrazolyl, pyrimidyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, naphthyridyl (e.g., 1, 5 or 1,7), pyrido[2,3]imidazolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, pyridopyrimidinyl,7-azaindolyl and the like. The term “heteroaryl” also refers topartially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. All positionalisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.

It should be noted that in heterocycloalkyl ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5. Seeparagraph below and make sure it is okay.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

When R⁴ and R⁵ are joined together to form a 5-7 membered carbocyclicring that is fused to the pyridyl ring to which R⁴ and R⁵ are attached,“carbocyclic” means a cycloalkyl, aryl or partially unsaturated ringcomposed of 5-7 carbon atoms wherein two of the carbons are sharedbetween the fused rings. When R⁴ and R⁵ are joined together to form a5-7 membered heterocyclic ring that is fused to the pyridyl ring towhich R⁴ and R⁵ are attached, “heterocyclic” means a fully saturated,partially saturated or aromatic ring composed of carbon atoms and one,two or three heteroatoms selected from N, S, or O, wherein two of thecarbons are shared between the fused rings. Representative ringsinclude:

When a moiety can be optionally substituted, it means that each carbonand heteroatom (when present) available for substitution in the givenmoiety may be independently unsubstituted or substituted with specifiednumber of substituents that are the same or different at each occurrenceand which result in the creation of a stable structure as is understoodto be reasonable by one skilled in the art.

Unless expressly depicted or described otherwise, variables depicted ina structural formula with a “floating” bond, such as R² structuralFormula III, are permitted on any available carbon atom in the ring towhich each is attached.

When R⁸ and R⁹ together with the nitrogen to which they are attachedform a saturated 5- to 7-membered heterocyclic ring, this means asaturated heterocyclic ring composed of, in addition to the one nitrogenatom, carbon atoms and optionally one additional heteroatom selectedfrom N, S or O. Representative examples include:

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I. Centers of asymmetry that are present in thecompounds of Formula I can all independently of one another have (R)configuration or (S) configuration. When bonds to the chiral carbon aredepicted as straight lines in the structural formulae of the invention,it is understood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the formula. Similarly, when a compound name is recited without achiral designation for a chiral carbon, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. Theproduction of specific stereoisomers or mixtures thereof may beidentified in the Examples where such stereoisomers or mixtures wereobtained, but this in no way limits the inclusion of all stereoisomersand mixtures thereof from being within the scope of this invention.

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I or it can be done on a finalracemic product. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing astereogenic center of known configuration. Where compounds of thisinvention are capable of tautomerization, all individual tautomers aswell as mixtures thereof are included in the scope of this invention.The present invention includes all such isomers, as well as salts,solvates (including hydrates) and solvated salts of such racemates,enantiomers, diastereomers and tautomers and mixtures thereof.

Reference to the compounds of this invention as those of a specificformula or embodiment, e.g., Formula I (which includes the compounds ofFormulae II-V) or any other generic structural formula or specificcompound described or claimed herein, is intended to encompass thespecific compound or compounds falling within the scope of the formulaor embodiment, including salts thereof, particularly pharmaceuticallyacceptable salts, solvates of such compounds and solvated salt formsthereof, where such forms are possible unless specified otherwise.

In the compounds of Formula I, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of Formula I. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin Formula I can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

When the compounds of Formula I contain one or more acidic or basicgroups the invention also includes the corresponding physiologically ortoxicologically acceptable salts, in particular the pharmaceuticallyacceptable salts. Thus, the compounds of Formula I which contain acidicgroups can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Examplesof such salts include but are not limited to sodium salts, potassiumsalts, calcium salts, magnesium salts or salts with ammonia or organicamines such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of Formula I which contain one or more basicgroups, i.e. groups which can be protonated, can be used according tothe invention in the form of their acid addition salts with inorganic ororganic acids as, for example but not limited to, salts with hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid,benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroaceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, etc. If the compounds ofFormula I simultaneously contain acidic and basic groups in the moleculethe invention also includes, in addition to the salt forms mentioned,inner salts or betaines (zwitterions). Salts can be obtained from thecompounds of Formula I by customary methods which are known to theperson skilled in the art, for example by combination with an organic orinorganic acid or base in a solvent or dispersant, or by anion exchangeor cation exchange from other salts. The present invention also includesall salts of the compounds of Formula I which, owing to lowphysiological compatibility, are not directly suitable for use inpharmaceuticals but which can be used, for example, as intermediates forchemical reactions or for the preparation pharmaceutically acceptablesalts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I areintended to be included within the scope of the present invention. Inaddition, some of the compounds of the instant invention may formsolvates with water (i.e., a hydrate) or common organic solvents. Suchsolvates and hydrates, particularly the pharmaceutically acceptablesolvates and hydrates, of the instant compounds are likewise encompassedwithin the scope of this invention, along with un-solvated and anhydrousforms.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid group or by formation of an ester on anavailable hydroxy group in a compound. Similarly, labile amides can bemade. Pharmaceutically acceptable esters or amides of the compounds ofthis invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO-depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.Examples of pharmaceutically acceptable pro-drug modifications include,but are not limited to, —C₁₋₆alkyl esters and —C₁₋₆alkyl substitutedwith phenyl esters.

Accordingly, the compounds within the generic structural formulas,embodiments and specific compounds described and claimed hereinencompass salts, all possible stereoisomers and tautomers, physicalforms (e.g., amorphous and crystalline forms), solvate and hydrate formsthereof and any combination of these forms, as well as the saltsthereof, pro-drug forms thereof, and salts of pro-drug forms thereof,where such forms are possible unless specified otherwise.

Compounds of the present invention are effective at inhibiting thesynthesis of aldosterone by inhibiting CYP11B2 (aldosterone synthase)and they are therefore useful agents for the therapy and prophylaxis ofdisorders that are associated with elevated aldosterone levels.Accordingly, an embodiment of the instant invention is to provide amethod for inhibiting aldosterone synthase, and more particularlyselectively inhibiting CYP11B2, in a patient in need thereof, comprisingadministering a compound of Formula I to the patient in an amounteffective to inhibit aldosterone synthesis, or more particularly toselectively inhibit CYP11B2, in the patient. A selective inhibitor ofCYP11B2 is intended to mean a compound that preferentially inhibitsCYP11B2 as compared to CYP11B1. The inhibition of CYP11B2, as wellinhibition of CYP11B1, by the compounds of Formula I can be examined,for example, in the inhibition assays described below.

In general, compounds that have activity as aldosterone synthaseinhibitors can be identified as those compounds which have an IC₅₀ ofless than or equal to about 10 μM; preferably less than or equal toabout 250 nM; and most preferably less than or equal to about 100 nM, inthe V79-Human-CYP11B2 Assay described below. In general, aldosteronesynthase inhibitors that are selective for inhibition of CYP11B2 ascompared to CYP11B1 are those that show at least 3-fold greaterinhibition for CYP11B2 compared to CYP11B1; preferably at least 20-foldinhibition for CYP11B2 compared to CYP11B1; and more preferably at least100-fold greater inhibition for CYP11B2 compared to CYP11B1, in theV79-Human-CYP11B2 Assay as compared to the V79-Human-CYP11B1 Assay.

Due to their ability to inhibit CYP11B2, the compounds of the presentinvention may be useful to treat and/or ameliorate the risk forhypertension, hypokalemia, renal failure (e.g., chromic renal failure),restenosis, Syndrome X, nephropathy, post-myocardial infarction,coronary heart diseases, increased formation of collagen, fibrosis andremodeling following hypertension and endothelial dysfunction,cardiovascular diseases, renal dysfunction, liver diseases, vasculardiseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, heart failure (e.g., congestiveheart failure), diastolic heart failure, left ventricle diastolicdysfunction, diastolic heart failure, systolic dysfunction, ischemia,myocardial and vascular fibrosis, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, cardiaclesions, vascular wall hypertrophy, endothelial thickening or necrosisof coronary arteries.

The dosage amount of the compound to be administered depends on theindividual case and is, as is customary, to be adapted to the individualcircumstances to achieve an optimum effect. Thus, it depends on thenature and the severity of the disorder to be treated, and also on thesex, age, weight and individual responsiveness of the human or animal tobe treated, on the efficacy and duration of action of the compoundsused, on whether the therapy is acute or chronic or prophylactic, or onwhether other active compounds are administered in addition to compoundsof Formula I. A consideration of these factors is well within thepurview of the ordinarily skilled clinician for the purpose ofdetermining the therapeutically effective or prophylactically effectivedosage amount needed to prevent, counter, or arrest the progress of thecondition. It is expected that the compound will be administeredchronically on a daily basis for a length of time appropriate to treator prevent the medical condition relevant to the patient, including acourse of therapy lasting days, months, years or the life of thepatient.

In general, a daily dose of approximately 0.001 to 30 mg/kg, preferably0.001 to 20 mg/kg, in particular 0.01 to 10 mg/kg (in each case mg perkg of bodyweight) is appropriate for administration to an adult weighingapproximately 75 kg in order to obtain the desired results. The dailydose is preferably administered in a single dose or, in particular whenlarger amounts are administered, can be divided into several, forexample two, three or four individual doses, and may be, for example butnot limited to, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 2 mg,2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, etc., on adaily basis. In some cases, depending on the individual response, it maybe necessary to deviate upwards or downwards from the given daily dose.

The term “patient” includes animals, preferably mammals and especiallyhumans, who use the instant active agents for the prevention ortreatment of a medical condition. Administering of the drug to thepatient includes both self-administration and administration to thepatient by another person. The patient may be in need of treatment foran existing disease or medical condition, or may desire prophylactictreatment to prevent or reduce the risk of said disease or medicalcondition.

The term “therapeutically effective amount” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.A “prophylactically effective amount” is intended to mean that amount ofa pharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. The terms “preventing” or “prevention” areused herein refer to administering a compound before the onset ofclinical symptoms.

It is understood that a specific daily dosage amount can simultaneouslybe both a therapeutically effective amount, e.g., for treatment ofhypertension, and a prophylactically effective amount, e.g., forprevention of myocardial infarction.

In the methods of treatment of this invention, the compound may beadministered via any suitable route of administration such as, forexample, orally, parenterally, or rectally in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. Oral formulations are preferred,particularly solid oral dosage units such as pills, tablets or capsules.

Accordingly, this invention also provides for pharmaceuticalcompositions comprised of a compound of Formula I and a pharmaceuticallyacceptable carrier. For oral use, the pharmaceutical compositions ofthis invention containing the active ingredient may be in forms such aspills, tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules, orsyrups or elixirs. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients, which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose,mannitol, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc.Pharmaceutical compositions may also contain other customary additives,for example, wetting agents, stabilizers, emulsifiers, dispersants,preservatives, sweeteners, colorants, flavorings, aromatizers,thickeners, diluents, buffer substances, solvents, solubilizers, agentsfor achieving a depot effect, salts for altering the osmotic pressure,coating agents or antioxidants.

Oral immediate-release and time-controlled release dosage forms may beemployed, as well as enterically coated oral dosage forms. Tablets maybe uncoated or they may be coated by known techniques for aestheticpurposes, to mask taste or for other reasons. Coatings can also be usedto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Oilysuspensions may be formulated by suspending the active ingredient in avegetable oil, for example arachis oil, olive oil, sesame oil or coconutoil, or in mineral oil such as liquid paraffin. The oily suspensions maycontain a thickening agent, for example beeswax, hard paraffin or cetylalcohol. Sweetening agents and flavoring agents may be added to providea palatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid. Syrups and elixirsmay be formulated with sweetening agents, for example glycerol,propylene glycol, sorbitol or sucrose.

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining a compound of Formula Iwith a pharmaceutically acceptable carrier. Also encompassed is thepharmaceutical composition which is made by combining a compound ofFormula I with a pharmaceutically acceptable carrier. The carrier iscomprised of one or more pharmaceutically acceptable excipients.Furthermore, a therapeutically effective amount of a compound of thisinvention can be used for the preparation of a medicament useful forinhibiting aldosterone synthase, inhibiting CYP11B2, for normalizing adisturbed aldosterone balance, or for treating or preventing any of themedical conditions described herein, in dosage amounts described herein.

The amount of active compound of Formula I and its pharmaceuticallyacceptable salts in the pharmaceutical composition may be, for examplebut not limited to, from 0.1 to 200 mg, preferably from 0.1 to 50 mg,per dose on a free acid/free base weight basis, but depending on thetype of the pharmaceutical composition and potency of the activeingredient it could also be lower or higher. Pharmaceutical compositionsusually comprise 0.5 to 90 percent by weight of the active compound on afree acid/free base weight basis.

Since the compounds of Formula I inhibit aldosterone synthase, apartfrom use as pharmaceutically active compounds in human medicine andveterinary medicine, they can also be employed as a scientific tool oras aid for biochemical investigations in which such an effect onaldosterone synthase and aldosterone levels is intended, and also fordiagnostic purposes, for example in the in vitro diagnosis of cellsamples or tissue samples. The compounds of Formula I can also beemployed as intermediates for the preparation of other pharmaceuticallyactive compounds.

One or more additional pharmacologically active agents (or therapeuticagents) may be administered in combination with a compound of Formula I.An additional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) different from the compound ofFormula I. Generally, any suitable additional active agent or agents,including but not limited to anti-hypertensive agents,anti-atherosclerotic agents such as a lipid modifying compound,anti-diabetic agents and/or anti-obesity agents may be used in anycombination with the compound of Formula I in a single dosageformulation (a fixed dose drug combination), or may be administered tothe patient in one or more separate dosage formulations which allows forconcurrent or sequential administration of the active agents(co-administration of the separate active agents). Examples ofadditional active agents which may be employed include but are notlimited to angiotensin converting enzyme (ACE) inhibitors (e.g,alacepril, benazepril, captopril, ceronapril, cilazapril, delapril,enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexepril,moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril); dual inhibitors of angiotensin converting enzyme (ACE)and neutral endopeptidase (NEP) such as omapatrilat, sampatrilat andfasidotril; angiotensin II receptor antagonists (e.g., candesartan,eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan)neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon),aldosterone antagonists, renin inhibitors (e.g., enalkrein, RO 42-5892,A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, vasodilators, calcium channel blockers (e.g., amlodipine,bepridil, diltiazem, felodipine, gallopamil, nicardipine, nifedipine,niludipine, nimodipine, nisoldipine veraparmil), potassium channelactivators (e.g., nicorandil, pinacidil, cromakalim, minoxidil,aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide) includingloop diuretics such as ethacrynic acid, furosemide, bumetanide andtorsemide, sympatholitics, beta-adrenergic blocking drugs (e.g.,acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol,metoprolol tartate, nadolol, propranolol, sotalol, timolol); alphaadrenergic blocking drugs (e.g., doxazocin, prazocin or alphamethyldopa) central alpha adrenergic agonists, peripheral vasodilators(e.g. hydralazine); lipid lowering agents (e.g., simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®),and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium; niacin inimmediate-release or controlled release forms, and particularly inniacin in combination with a DP antagonist such as laropiprant(TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niacinreceptor agonists such as acipimox and acifran, as well as niacinreceptor partial agonists; metabolic altering agents including insulinsensitizing agents and related compounds (e.g., muraglitazar, glipizide,metformin, rosiglitazone), dipeptidyl peptidase 4 inhibitors (e.g.,sitagliptin, alogliptin, vildagliptin, saxagliptin, linagliptin,dutogliptin, and gemigliptin); or with other drugs beneficial for theprevention or the treatment of the above-mentioned diseases includingnitroprusside and diazoxide.

In general, the compounds in the invention may be produced by a varietyof processes know to those skilled in the art and by know processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods and one skilled in the artwould have resources such as Chemical Abstracts or Beilstein at his orher disposal to assist in devising an alternative method of preparing aspecific compound.

The compounds of the present invention can be prepared according to theprocedures of the following Schemes using appropriate materials and arefurther exemplified by the specific Examples which follow. Moreover, byutilizing the procedures described herein, one of ordinary skill in theart can readily prepare additional compounds of the present inventionclaimed herein.

Throughout the synthetic schemes, abbreviations are used with thefollowing meanings unless otherwise indicated:

AcCN=acetonitrile; aq=aqueous, Ar=aryl; BSA=bovine serum albumin;Bu=butyl, t-Bu=tert-butyl; n-BuLi=n-butyllithium; conc,conc.=concentrated; c-Pr=cyclopropyl; Cy=cyclohexyl;dba=dibenzylideneacetone; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene;DCM=dichloromethane; DECALIN=decahydronaphthalene; DIPA=diisopropylamine; DMEM=Dulbecco's modified eagle medium; DMF=N,N-dimethylformamide;DMSO=dimethylsulfoxide; DPPF=1.1-bis(diphenylphosphino)ferrocene;eq.=equivalent(s); EDTA=ethylenediaminetetraacetic acid; Et=ethyl;EtOAc=ethyl acetate; EtOH=ethanol; FBS=Fetal Bovine Serum; h, hr=hour;HPLC=High pressure liquid chromatography; HTRF=homogenous time resolvedfluorescence; i-PrOH=isopropanol; i-Pr=isopropyl; KHMDS=Potassiumbis(trimethylsilyl)amide; LCMS=liquid chromatography-mass spectroscopy;Me=methyl; MeOH=methanol; min, min.=minute; MS=mass spectroscopy;MTBA=methyl ternary-butyl ether; MW=microwave; NCS=N-chlorosuccinimide;NMR=nuclear magnetic resonance; PBS=phosphate buffered saline;PdCl₂(dppf)=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II);Pd(dppf)₂Cl₂.DCM=1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane;Pd₂(dba)₃=tris(dibenzylidineacetone)dipalladium; Pd/C=palladium onactivated carbon; Ph=phenyl; Pr=propyl; Prep TLC=preparatice thin layerchromatography; Py=pyridyl;PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; OAc=acetate; RT, rt=room temperature;sat.=saturated; S-Phos=2-dichlorocyclohexylphosphino-2′,6′-dimethoxybiphenyl; TBAF=tetrabutylammonium fluoride;TEA=triethyl amine; THF=tetrahydrofuran; triflate, TFA=trifluoroaceticacid and TfO₂=trifluoromethanesulfonic anhydride.

As will be known to those skilled in the art, in all schemes, theproducts of Formula I and all synthetic intermediates may be purifiedfrom unwanted side products, reagents and solvents by recrystallization,trituration, preparative thin layer chromatography, flash chromatographyon silica gel as described by W. C. Still et al, J. Org. Chem. 1978, 43,2923, or reverse-phase HPLC. Compounds purified by HPLC may be isolatedas the corresponding salt.

Additionally, in some instances the final compounds of Formula I andsynthetic intermediates may be comprised of a mixture of cis and transisomers, enantiomers or diastereomers. As will be known to those skilledin the art, such cis and trans isomers, enantiomers and diastereomersmay be separated by various methods including crystallization,chromatography using a homochiral stationary phase and, in the case ofcis/trans isomers and diastereomers, normal-phase and reverse-phasechromatography.

Chemical reactions were monitored by LCMS, and the purity and identityof the reaction products were assayed by LCMS (electrospray ionization)and NMR. LCMS spectra were recorded in some instances on an Agilent 1100series instrument equipped with an Xterra MS C18 column (3.5 μM, 3.0×50mm i.d.) and UV detector. 1H NMR spectra were recorded, for example, ona Varian 500 HHz spectrometer and are internally referenced to residualprotio solvent signals. Data for ¹H NMR are reported with chemical shift(δ ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, br s=broad singlet, br m=broad multiplet), couplingconstant (Hz), and integration. Unless otherwise noted, all LCMS ionslisted are [M+H]. All temperatures are degrees Celsius unless otherwisenoted.

In the Examples, some intermediates and final compounds having a chiralcarbon were prepared as racemates, and some chiral intermediates wereresolved and the enantiomers were used separately to synthesizeenantiomeric downstream intermediates and final products. In some casesracemic final products may have been resolved. In the instances wherechiral compounds were separated by chiral HPLC purification, the term“enantiomer A” or “ent A” refers to the first eluting enantiomer and thedownstream compounds derived from this enantiomer. The term “enantiomerB” or “ent B” refers to the second eluting enantiomer and the downstreamcompounds derived from this enantiomer. The term “rac” refers to aracemic mixture. As a result, the chemical nomenclature may indicatethat an S and/or an R enantiomer was obtained, but the absolutestereochemistry of the separate enantiomers A and/or B was notdetermined.

Preparative HPLC was performed, for example, using a SunFire Prep C18OBD column (5 μM, 19×100 mm i.d.) on Gilson instruments equipped with UVdetectors.

Flash chromatography on silica gel was performed, for example, usingpre-packed silica gel columns on Biotage Horizon or Biotage SP-1instruments equipped with UV detectors.

The following examples are provided so that the invention might be morefully understood. They should neither be construed as forming the onlygenus that is considered as the invention nor limiting the invention inany way.

2-Heteroaryl triazolopyridines can be synthesized according to Scheme 1.Treatment of appropriately substituted pyridine 1 withO-(mesitylenesulfonyl) hydroxylamine yields aminopyridinium salt 2.Reaction of 2 with an appropriately substituted cyanopyridine yields thedesired 2-heteroaryl triazolopyridine 3.

Alternatively to Scheme 1, 2-heteroaryl triazolopyridines can also besynthesized according to Scheme 2. Treatment of 2-amino pyridine 4 withan appropriately substituted cyanopyridine yieldsN-(2-pyridyl)nicotinamidine 5 which upon treatment with lead tetracetateaffords the desired 2-heteroaryl triazolopyridine 6.

2-(Pyridin-3-yl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onesmay be prepared according to Scheme 3. Initial Suzuki coupling between5-amino-3-bromo-1H-pyrazole-4-carbonitrile 7 and a pyridyl boronic acidmay afford the coupled pyrdinyl triazole 8. Treatment of 8 with ethylacrylate may then yield N-alkylated product 9. Ring closure of 9 uponreaction with n-butyl lithium may afford2-(pyridin-3-yl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one10, which may undergo further modification such as alkyation with anelectrophile such as methyl iodide to yield 11.

The cyanopyridines employed in these reactions may be obtainedcommercially, prepared by reactions known in literature or prepared bymodifying reactions known in the art. Scheme 4 depicts one method, forexample, by which one of ordinary skill in the art might be able toprepare a cyanopyridine:

3,5-Dibromopyridine 12 is treated with n-butyllithium and acetone in asolvent such as toluene at low temperature to provide 13. Heating ofbromide 13 and zinc cyanide in the presence of a catalyst such astetrakis(triphenlyphosphine)palladium(0) in a solvent such asacetonitrile then affords cyanopyridine 14.

The heteroaryl boronic acids or esters employed in these reactions maybe obtained commercially, prepared by reactions known in literature orprepared by modifying reactions known in the art. Scheme 5 depicts onemethod, for example, by which one or ordinary skill in the art might beable to prepare a boronic ester:

Treating 3,5-dibromopyridine 15 with n-butyllithium and acetone in asolvent such as toluene at low temperature provides 16. Heating bromide16 and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in thepresence of a catalyst such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) and a basesuch as potassium acetate in a solvent such as 1,4-dioxane then affordsboronate ester 17.

Scheme 6 describes an alternative method for the preparation of pyridylboronic acids:

1-(5-Bromopyridin-3-yl)ethanone 18 is treated with(trifluoromethyl)trimethylsilane and tetrabutylammonium fluoride in asolvent such as tetrahydrofuran to provide 19. Heating of bromide 19 and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in thepresence of a catalyst such as tris(dibenzylideneacetone)dipalladium(0), a ligand such as tricyclohexylphosphine, and a base such aspotassium acetate in a solvent such as 1,4-dioxane then affords boronicacid 20.

As will be known to those skilled in the art, in all schemes, theproducts of Formula I and all synthetic intermediates may be purifiedfrom unwanted side products, reagents and solvents by recrystallisation,trituration, preparative TLC, flash chromatography on silica gel orreverse-phase HPLC. Compounds purified by HPLC may be isolated as thecorresponding salt.

The following is illustrative of the processes used for making some ofthe intermediates employed in the examples below:

Intermediate C

Synthesis of 3-Bromo-4-cyclopropyl-5-fluoro-4H-pyridine-1-carboxylicacid phenyl ester (A)

Phenyl chloroformate (4.2 mL, 0.033 mol) was added to a mixture of3-bromo-5-fluoro-pyridine (5.5 g, 0.031 mol), dimethyl sulphide (15.32mL, 0.209 mol) and copper iodide (5.95 g, 0.031 mol) in anhydroustetrahydrofuran (50 mL) at RT and the reaction mixture was stirred for40-50 min. To this suspension, cyclopropylmagnesiumbromide (66.75 mL,0.033 mol, 0.5 M solution in tetrahydrofuran) was added at −25 to −20°C. over a 30-40 min period. The mixture was stirred at this temperaturefor 30 min, and then warmed slowly to RT over 1.0-1.5 hrs. The reactionmixture was quenched with a saturated aqueous ammonium chloride solution(200 mL), followed by extraction of the aqueous layer with ethyl acetate(3×200 mL). The combined organic layers were washed with a saturatedaqueous sodium chloride solution (2×100 mL), and dried over anhydroussodium sulphate to afford the crude compound, which was purified bysilica gel chromatography using 0-5% ethyl acetate-hexane gradient. Thisyielded crude phenyl3-bromo-4-cyclopropyl-5-fluoro-4H-pyridine-1-carboxylic acid phenylester.

Synthesis of 3-Bromo-4-cyclopropyl-5-fluoro-pyridine (B)

A mixture of crude3-bromo-4-cyclopropyl-5-fluoro-4H-pyridine-1-carboxylic acid phenylester (A; 7.5 g, 0.022 mol) and sulphur (0.71 g, 0.022 mol) were heatedat reflux in DECALIN (25 mL) for a period of 3 h and then cooled to RT.The reaction mixture was purified by silica gel column chromatography,eluting first with hexane and then with a 2-5% ethyl acetate-hexanegradient to afford 3-bromo-4-cyclopropyl-5-fluoro-pyridine. ¹H NMR (400MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.42 (s, 1H), 1.98-1.94 (m, 1H), 1.11-1.09(m, 2H), 0.99-0.98 (m, 2H). MS (M+1): 217.1.

Synthesis of 4-cyclopropyl-5-fluoronicotinonitrile (C)

Copper cyanide (0.829 g, 0.00925 mol) was added at RT to a sealed tubecontaining 3-bromo-4-cyclopropyl-5-fluoro-pyridine (B; 1 g, 0.00462 mol)in dimethylformamide (20 mL). The reaction mixture was heated to 150° C.for 18 hr, then cooled to RT, quenched with 20% aqueous ammonia (20 mL)solution, and stirred for 5 min. It was extracted with diethyl ether(2×100 mL). The combined organic layers were washed with water (2×50 mL)and dried over anhydrous sodium sulphate to afford4-cyclopropyl-5-fluoronicotinonitrile. MS (M+1): 163.1.

Intermediate D Synthesis of 5-cyclopropylnicotinonitrile (D)

Cesium carbonate (20.8 g, 0.064 mol) was added to a stirred solution of5-bromo-nicotinonitrile (6 g, 0.0322 mol) and cyclopropylboronic acid(2.8 g, 0.032 mol) in a mixture of 1,4-dioxan (100 mL) and water (50mL). The reaction vessel was purged with argon for 20 min andPd(dppf)₂Cl₂.DCM (1.3 g, 0.0016 mol) was added to the reaction mixture.The reaction vessel was purged again with argon for 10 min andsubsequently allowed to stir at 100° C. for 3 h. The reaction mixturewas filtered through a filter bed of CELITE and the filter bed wasthoroughly washed with ethyl acetate (3×200 mL). The collected organicfractions were concentrated under vacuum to afford the crude product,which was purified by silica gel column chromatography to afford5-cyclopropylnicotinonitrile. MS (M+1): 144.8.

Intermediate F Synthesis of 5-fluoro-4-methylnicotinonitrile (F)

Synthesis of 3-bromo-5-fluoro-4-methyl pyridine (E)

n-Butyllithium (46 mL, 0.0738 mol, 1.6 M) was added to a solution ofdiisopropylamine (10.08 mL, 0.0738 mol) in tetrahydrofuran (80 mL) at−78° C. The reaction mixture was warmed to 0° C., stirred for 30 min,and then cooled to −78° C. 3-Bromo-5-fluoro-pyridine (10.0 g, 0.056 mol)in tetrahydrofuran (10 mL) was added to the reaction mixture and thereaction mixture was stirred for 30 min. Methyl iodide (4 mL, 0.062 mol)was added to the reaction mixture at same temperature and the reactionmixture was then allowed to warm to RT and stirred it for 2 h. Thereaction mixture was quenched with a saturated aqueous ammonium chloridesolution (150 mL) solution. Then aqueous layer was extracted with ethylacetate (3×150 mL). The combined organic extracts were washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulphate and concentrated to afford 3-bromo-5-fluoro-4-methyl pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 3H). MS(M+2): 192.0.

Synthesis of 5-fluoro-4-methylnicotinonitrile (F)

Copper cyanide (1.87 g, 0.021 mol) was added at room temperature to asealed tube containing a solution of 3-bromo-5-fluoro-4-methylpyridine(E; 2.0 g, 0.0105 mol) in dimethylformamide (20 mL). The reactionmixture was heated to 150° C. for 16 h. It was then cooled to RT,quenched with 20% aqueous ammonia (30 mL) solution and stirred for 5min. The reaction mixture was extracted with diethyl ether (2×100 mL).The organic layers were washed with water (2×50 mL), dried overanhydrous sodium sulphate and concentrated to afford5-fluoro-4-methylnicotinonitrile. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (s,1H), 8.56 (s, 1H), 2.56 (s, 3H).

Intermediate G was synthesized following the synthetic procedure asdescribed above for Intermediate F

TABLE 1 LCMS Intermediate Structure IUPAC Name (M + 1) G

4-ethyl-5- fluoronicotinonitrile 151.1

Intermediate H Synthesis of 5-fluoronicotinonitrile (H)

Zn(CN)₂ (2.45 g, 0.020 mol) and 1,1′-bis(diphenylphosphino)ferrocene(0.045 g, 0.0008 mol) were added to a solution of 3-bromo-5-fluoropyridine (3.5 g, 0.0198 mol) in dimethylformamide. The reaction vesselwas purged with argon for 10 min. Next, Pd₂(dba)₃ (0.04 g, 0.000043 mol)was added and the reaction vessel was purged with argon for another 5min. The reaction mixture heated to 130° C. for 40 min under microwaveirradiation. The reaction mixture was cooled to RT, diluted with water(100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (2×100 mL) and dried over sodium sulphate. The combined organiclayers were then concentrated under vacuum to get crude product, whichwas purified by silica gel column chromatography to afford5-fluoronicotinonitrile. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H),8.71-8.70 (d, J=4 Hz, 1H), 7.70-7.76 (d, J=4 Hz, 1H).

Intermediate I was synthesized following the synthetic procedure asdescribed above for Intermediate H

TABLE 2 LCMS Intermediate Structure IUPAC Name (M + 1) I

5-methyl nicotinonitrile 118.7

Intermediate K Synthesis of2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (K)

Synthesis of tert-butyl (mesitylsulfonyl)oxycarbamate (J)

2,4,6-trimethylbenzenesulfonyl chloride (5 g, 0.022 mol) was added to asolution of methyl tertiary-butyl ether (50 mL) under nitrogenatmosphere at 0° C., followed by the addition of tert-butylhydroxycarbamate (3.04 g, 0.22 mol) at 0° C. Next, triethylamine (3.24mL, 0.023 mol) was added drop wise to the reaction mixture, which wasthen it was allowed to stir for 2 h. The reaction product was filteredthrough sintered funnel and the filtrate was concentrated under vacuumup to 3 volume. Hexane (50 mL) was added to the concentrated filtrate,which was then stirred for 20 min wherein a precipitate formed. Theparticipate was collected by filtration and the solid dried to affordtert-butyl (mesitylsulfonyl)oxycarbamate. ¹H NMR (400 MHz, CDCl₃) δ 8.49(s, 1H), 8.31 (s, 1H), 2.38 (s, 9H). MS (M+1): 316.3.

Synthesis of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (K)

Trifluoroacetic acid (20 mL) was cooled to 0° C., then tert-butyl(mesitylsulfonyl) oxycarbamate (J; 6 g, 0.0189 mol) was added portionwise for 30 min. The reaction mixture was allowed to stir for 2 h at thesame temperature. Ice cold water (150 mL) was added and the reactionmixture was stirred for 15 min to form a precipitate, which was filteredto get a solid compound. The solid was dried under vacuum to afford2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene. ¹H NMR (400 MHz, CDCl₃) δ8.62 (s, 1H), 8.56 (s, 1H), 2.56 (s, 3H)

Intermediate L Synthesis of 5-fluoro-4-methylnicotinonitrile (L)

n-Butyl lithium (1.65 mL, 0.00265 mol, 1.6 M) was added to a solution of3-bromo-4-(trifluoromethyl)pyridine (E; 0.5 g, 0.022 mol) in anhydroustetrahydrofuran (15 mL), at −78° C. The reaction mixture was stirred for10 min followed by the addition of dimethlformamide (0.2 mL, 0.00265).It was stirred for 30 min at same temperature. The reaction mixture wasquenched with a saturated aqueous ammonium chloride solution (25 mL) andthe aqueous layer was extracted with ethyl acetate (2×50 mL). Theorganic extracts were combined and then washed with a saturated aqueoussodium chloride solution (1×50 mL), dried over sodiumsulphate andconcentrated to afford 4-(trifluoromethyl)nicotinaldehyde. ¹H NMR (400MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.25 (s, 1H), 9.10-9.09 (d, J=4 Hz, 1H),7.95-7.94 (d, J=4 Hz, 1H).

Intermediate M was synthesized following the synthetic procedure asdescribed above for Intermediate L.

TABLE 3 LCMS Intermediate Structure IUPAC Name (M + 1) M

4-ethyl-5- fluoronicotinaldehyde —

Example 1

Step A. 2-(5-bromopyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 2-picoline (200 mg, 2.15 mmol) in dichloromethane (2ml) was added o-(mesitylsulfonyl)hydroxylamine (462 mg, 2.148 mmol). Theresulting mixture was stirred at room temperature for 30 minutes, thenconcentrated under reduced pressure to give a crude product that wasused without further purification in the next reaction described below.

A mixture of the crude product described above and5-bromonicotinonitrile (393 mg, 2.15 mmol) in ethanol (2 ml) was cooledto 0° C. Aqueous potassium hydroxide solution (2.0 M, 1.073 ml, 2.147mmol) was then added. The resulting mixture was stirred at 0° C. for 1hour, then warmed to room temperature and stirred for 18 hours. Themixture was concentrated under reduced pressure, diluted withacetonitrile (15 mL) and water (5 ml), sonicated for several minutes,then filtered. Solids were collected and dried under reduced pressure toprovide the title compound: LCMS m/z 288.92 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃) δ 9.49 (s, 1H), 8.79 (s, 2H), 7.70 (d, J=8.5 Hz, 1H), 7.54 (dd,J=8.8, 7.2 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 2.90 (s, 3H).

Step B:2-(5-(4-fluorophenyl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a microwave vial were added the title compound from Example 35 Step A(20 mg, 0.069), 4-fluorophenylboronic acid (9.7 mg, 0.069 mmol),tetrakis(triphenlyphosphine)palladium(0) (4 mg, 0.003 mmol), sodiumcarbonate (14.7 mg, 0.138 mmol), acetonitrile (1 mL), and water (0.5mL). The vial was sealed and heated in a microwave reactor to 150° C.for 10 minutes. The organic layer was decanted off and purified byreverse-phase HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1%v/v trifluoroacetic acid) to provide the title compound: LCMS m/z 305.06[M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.95 (s,1H), 7.73-7.76 (m, 4H), 7.57 (dd, J=8.9, 7.1 Hz, 1H), 7.26 (d, J=8.6 Hz,1H), 6.97 (d, J=7.3 Hz, 1H), 2.92 (s, 3H).

Example 2

Step A. 2-(5-bromo-3-pyridinyl)-2-propanol

To a 5000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added a solution of 3,5-dibromopyridine(264 g, 1.12 mol) in toluene (3000 mL). The solution was cooled to −78°C., and a solution of n-butyllithium in hexanes (2.6 M, 475 mL, 1.24mol) was then added, giving a solution that was stirred for 2 hours at−78° C. Acetone (108 g, 1.86 mol) was then added. After 1 hour, thereaction mixture was quenched by addition of 350 mL saturated aqueousammonium chloride solution. The resulting solution was extracted withethyl acetate. The organic extracts were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure. Purification byflash chromatography on silica gel (ethyl acetate/petroleum ether1:10-1:5) provided the title compound: ¹H NMR (400 MHz, CDCl₃): δ 8.63(s, 1H), 8.56 (s, 1H), 8.01 (s, 1H), 1.61 (s, 6H).

Step B. 5-(2-methoxypropan-2-yl)nicotinonitrile

A mixture of sodium hydride (60%/oil, 111 mg, 2.78 mmol) intetrahydrofuran (2 ml) was cooled to 0° C. The title compound fromExample 36 Step A (300 mg, 1.39 mmol) was then added. The reaction waswarmed to room temperature for 30 minutes, then cooled to 0° C.Iodomethane (0.095 mL, 1.53 mmol) was added, and the reaction mixturewas then warmed to room temperature and stirred for 18 hours. Thereaction was poured into ethyl acetate and washed sequentially withwater and saturated aqueous sodium chloride solution. The organic layerwas separated, dried over MgSO₄, filtered and concentrated under reducedpressure to give a crude product that was used without furtherpurification in the next reaction described below.

To a microwave vial were added the crude product described above, zinccyanide (230 mg, 1.96 mmol), tetrakis(triphenlyphosphine)palladium(0)(75 mg, 0.065 mmol), and acetonitrile (1.5 ml). The vial was sealed, andthe resulting mixture was heated in a microwave reactor to 150° C. for30 minutes. The mixture was then poured into aqueous sodium hydroxidesolution (1.0 N, 2 mL). The organic layer was separated, filtered andpurified by reverse-phase HPLC (C18 column, 10 to 100%acetonitrile/water, both 0.1% v/v trifluoroacetic acid) to provide thetitle compound: LCMS m/z 177.01 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.89(d, J=2.1 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.25 (dd, J=2.1, 2.0 1H),3.17 (s, 3H), 1.58 (s, 6H).

Step C.6-fluoro-2-(5-(2-methoxypropan-2-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

A solution of 2-amino-5-fluoropyridine (63.6 mg, 0.567 mmol) intetrahydrofuran (2 mL) was cooled to −78° C. A solution ofn-butyllithium in tetrahydrofuran (2.5 M, 0.148 ml, 0.369 mmol) wasadded, and the resulting mixture was warmed to −40° C. for 15 minutes,then cooled to −78° C. A solution of the title compound from Example 2Step B (50.0 mg, 0.284 mmol) in tetrahydrofuran (2 mL) was then added,giving a mixture that was warmed to room temperature and stirred for 18hours. The reaction was then concentrated under reduced pressure to givea crude product that was used without further purification in the nextreaction described below.

To a microwave vial were added the crude product described above, leadtetraacetate (151 mg, 0.341 mmol), and toluene (2 mL). The vial wassealed, and the reaction mixture was heated in a microwave reactor to150° C. for 1 hour. The reaction mixture was then concentrated underreduced pressure to give a residue that was purified by reverse-phaseHPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/vtrifluoroacetic acid) to provide the title compound: LCMS m/z 286.96[M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 9.54 (d, J=1.5 Hz, 1H), 9.03 (s, 1H),8.95 (s, 1H), 8.64 (d, J=2.6 Hz, 3H), 7.87 (dd, J=9.9, 4.9 Hz, 1H), 7.61(ddd, J=9.9, 9.9, 2.2 Hz, 1H), 3.28 (s, 3H), 1.70 (s, 6H).

Examples listed below in Table 4 were prepared according to theprocedures given above for the preparation of Examples 1 and 2 using theappropriate commercially available starting materials.

TABLE 4 Example Structure Name LCMS 3

6-fluoro-2-(pyridin-3-yl)- [1,2,4]triazolo[1,5- a]pyridine 215.05 4

8-fluoro-2-(pyridin-3-yl)- [1,2,4]triazolo[1,5- a]pyridine 215.06 5

4-([1,2,4]triazolo[1,5- a]pyridin-2- yl)isoquinoline 247.15 6

4-(8-fluoro-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 265.05 7

4-(8-chloro-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 281.03 8

4-(8-methyl-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 261.08 9

8-phenyl-2-(pyridin-3- yl)-[1,2,4]triazolo[1,5- a]pyridine 273.05 10

4-(5-methyl-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 261.03 11

4-(6,8-dimethyl-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 274.7312

2-(5-(6-fluoro-[1,2,4] triazolo[1,5-a]pyridin-2-yl)pyridin-3-yl)propan-2- ol 273.05 13

2-(5-bromopyridin-3-yl)- 5-methyl-[1,2,4] triazolo[1,5-a]pyridine 288.9214

2-(5-(2-methoxyphenyl) pyridin-3-yl)-5-methyl- [1,2,4]triazolo[1,5-a]pyridine 317.06 15

5-methyl-2-(5- phenylpyridin-3-yl)- [1,2,4]triazolo[1,5- a]pyridine287.05 16

5-methyl-2-(5-(4- (trifluoromethyl)phenyl) pyridin-3-yl)-[1,2,4]triazolo[1,5- a]pyridine 355.01 17

4-(5-methoxy-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 276.65 18

4-(6,8-difluoro-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 282.6119

6-fluoro-2-(5- (trifluoromethyl)pyridin- 3-yl)-[1,2,4]triazolo[1,5-a]pyridine 282.92 20

4-(7-fluoro-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 265.05 21

4-(6-fluoro-[1,2,4] triazolo[1,5-a]pyridin-2- yl)isoquinoline 265.05

Example 22

Step A. N-(5-Fluoro-pyridin-2-yl)-4-methyl-nicotinamidine

n-Butyllithium (1.6 M, 3.33 mL, 0.00534 mol) was added slowly for aperiod of 5 min at a temperature of at −78° C. to a solution of5-fluoro-pyridin-2-ylamine (0.3 g, 0.00267 mol) in anhydroustetrahydrofuran (20 mL). Then the temperature raised to −40° C. and thereaction mixture was stirred for 15 min. The reaction mixture was cooledto −78° C. and 4-methyl-nicotinonitrile (0.316 g, 0.00267 mol) intetrahydrofuran (5 mL) was added. The temperature was raised to RT andstirred for 18 h. The reaction mixture quenched with a saturated aqueousammonium chloride solution (25 mL) and then extracted with ethyl acetate(2×50 mL). The combined organic layer were dried over sodium sulphateand concentrated under vacuum to afford the crude product,N-(5-fluoro-pyridin-2-yl)-4-methyl-nicotinamidine, which was usedwithout further purification in the next step. MS (M+1): 231.1.

Step B.6-fluoro-2-(4-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

Lead tetra acetate (0.0693 g, 0.000156 mol) was added to a solution ofN-(5-fluoro-pyridin-2-yl)-4-methyl-nicotinamidine (22-1; 0.360 g, crude0.000156 mol) in toluene (10 mL) in a 40 mL microwave vial at RT. Thereaction mixture heated to 150° C. for 1.5 h under microwaveirradiation. The reaction mixture cooled to RT, diluted with water (50mL) and extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried over sodium sulphate and concentrated under vacuum toafford the crude product, which was purified by silica gel columnchromatography to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ9.40-9.38 (t, J=8 Hz, 1H), 9.12 (s, 1H), 8.51-8.50 (d, J=4 Hz, 1H),8.00-7.97 (m, J=12 Hz, 1H), 7.75-7.80 (t, J=20 Hz, 1H), 7.40-7.39 (d,J=4 Hz, 1H), 2.68 (s, 3H). MS (M+1): 229.1.

The compounds in Table 5 were prepared using the chemistry described inExample 22.

TABLE 5 LCMS Ex Structure IUPAC Name (M + 1) 23

2-(4-ethyl-5-fluoro pyridin-3-yl)-6- fluoro[1,2,4]triazolo[1,5-a]pyridine 261.2 24

2-(5-cyclopropyl pyridin-3-yl)-7- fluoro[1,2,4] triazolo[1,5-a] pyridine255.2 25

7-fluoro-2-(4-methyl pyridin-3-yl)[1,2,4] triazolo[1,5-a] pyridine 229.226

2-(4-ethyl-5- fluoropyridin-3-yl)- 7-fluoro[1,2,4] triazolo[1,5-a]pyridine 261.2 27

7-fluoro-2-(5- methylpyridin-3- yl)[1,2,4]triazolo [1,5-a]pyridine 229.228

2-(4-cyclopropyl-5- fluoropyridin-3-yl)- 7-fluoro[1,2,4] triazolo[1,5-a]pyridine 273.2 29

7-fluoro-2-(5-fluoro- 4-methylpyridin-3- yl)[1,2,4]triazolo[1,5-a]pyridine 247.2 30

6-chloro-2-pyridin-3- yl[1,2,4]triazolo[1,5- a]pyridine 231.6 31

6-chloro-2-(5- methylpyridin-3- yl)[1,2,4]triazolo [1,5-a]pyridine 245.632

6-chloro-2-(4- methyl pyridin-3-yl)[1,2,4] triazolo[1,5-a] pyridine245.6 33

6-chloro-7-methyl-2- (5-methylpyridin-3- yl)[1,2,4]triazolo[1,5-a]pyridine 259.7 34

6-chloro-2-(5- fluoropyridin-3-yl)- 7-methyl[1,2,4] triazolo[1,5-a]pyridine 263.6 35

2-(4-ethyl-5- fluoropyridin-3-yl)- 7-methyl[1,2,4] triazolo[1,5-a]pyridine 257.2 36

2-(5-bromopyridin-3- yl)-7-methyl[1,2,4] triazolo[1,5-a] pyridine 290.137

2-(5-cyclopropyl pyridin-3-yl)-7- methyl[1,2,4] triazolo[1,5-a ]pyridine251.2 38

7-methyl-2-(5- methylpyridin-3-yl) [1,2,4]triazolo[1,5-a] pyridine 225.239

2-(5-fluoropyridin-3- yl)-7-methyl[1,2,4] triazolo[1,5-a] pyridine 229.2

Example 40

Step A.N-4-chloropyridin-2-yl)-5-fluoro-4-methylpyridine-3-carboximidamide

Potassium bis(trimethylsilyl)amide (1.0 M, 4.1 mL, 0.0041 mol) was addedslowly for a period of 5 min to a solution of 4-chloro pyridin-2-amine(0.35 g, 0.00273 mol) in anhydrous tetrahydrofuran (30 mL) at 0° C. andstirred for 15 min at same temperature. Then4-methyl-5-fluoronicotinonitrile (0.37 g, 0.00273 mol) intetrahydrofuran (5 mL) was added. The reaction temperature was raised toRT and the reaction mixture was stirred it for 18 h. The reactionmixture was quenched with a saturated aqueous ammonium chloride solution(30 mL) and extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried over sodium sulphate and concentrated under vacuum toafford the crude product, which was purified by silica gel columnchromatography to afford the title compounds. ¹H NMR (400 MHz, CDCl₃) δ10.60 (bs, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.25-8.24 (d, J=4 Hz, 1H),7.25-7.24 (d, J=4 Hz, 1H), 7.02-7.00 (d, J=4 Hz, 1H), 2.48 (s, 3H), MS(M+1): 265.1.

Step B.7-chloro-2-(5-fluoro-4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

Lead tetra acetate (0.15 g, 0.00034 mol) was added at RT to a solutionof N-(4-chloropyridin-2-yl)-5-fluoro-4-methylnicotinimidamide (40-1;0.09 g, 0.00034 mol) in toluene (10 mL) in a 40 mL microwave vial. Thereaction mixture was heated to 150° C. for 1.5 h under microwaveirradiation. It was then cooled to RT, diluted with water (20 mL), andextracted with ethyl acetate (2×30 mL). the combined organic layers weredried over sodium sulphate and concentrated under vacuum to afford thecrude product, which was purified by Prep TLC to obtain the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10-9.086 (d, J=8 Hz, 1H), 9.01(s, 1H), 8.6 (s, 1H), 8.17 (s, 1H), 7.37-7.35 (d, J=8 Hz, 1H), 2.64 (s,3H), MS (M+1): 263.7.

Example 41 was synthesized following the synthetic procedure asdescribed above in Example 40.

TABLE 5 LCMS Ex Structure IUPAC Name (M + 1) 41

7-chloro-2-(4-methyl pyridin-3-yl)[1,2,4] triazolo[1,5-a]pyridine 245.6

Example 42

Step A. N-(4-chloropyridin-2-yl)-5-cyclopropylnicotinimidamide

n-Butyllithium (1.6 M, 2.2 mL, 0.0034 mol) was added slowly for a periodof 5 min to a solution of 4-chloropyridin-2-amine (0.4 g, 0.0031 mol) inanhydrous tetrahydrofuran (20 mL) at −78° C. The reaction temperaturewas raised to −40° C. and stirred for 15 min. The reaction mixture wascooled to −78° C. and 5-cyclopropyl-nicotinonitrile (0.45 g, 0.0031 mol)in tetrahydrofuran (5 mL) was added. The temperature was raised to RTand stirred it for 3 h. The reaction mixture was quenched with asaturated aqueous ammonium chloride solution (25 mL) then extracted withethyl acetate (2×50 mL). The combined organic layers were dried oversodium sulphate and concentrated under vacuum to afford the crudeproduct, which was recrystallised with a DCM and ether mixture to affordthe title compound. MS (M−1): 271.0.

Step B.7-chloro-2-(5-cyclopropylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

Lead tetra acetate (0.684 g, 0.0015 mol) was added to a solution ofN-(4-chloropyridin-2-yl)-5-cyclopropylnicotinimidamide (42-1; 0.280 g,0.001 mol) in toluene (30 mL) in a 40 mL microwave vial at RT. Thereaction mixture was heated to 150° C. for 2 h under microwaveirradiation. It was cooled to RT then diluted with water (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layer wasdried over sodium sulphate and concentrated under vacuum to afford thecrude product, which was purified by silica gel column chromatography toafford the title compound. ¹H NMR (400 MHz, DMSO) δ 9.08-9.02 (t, J=7.2Hz, 2H), 8.52 (s, 1H), 8.10-8.05 (d, J=18.4 Hz, 2H), 7.32-7.31 (d, J=6.8Hz, 1H), 2.08 (s, 1H), 1.07-1.05 (d, J=10.4 Hz, 2H), 0.82-0.81 (d, J=4.4Hz, 2H). MS (M+1): 271.7.

Example 43 was synthesized following the synthetic procedure asdescribed above for Example 42.

TABLE 7 LCMS Ex Structure IUPAC Name (M + 1) 43

7-chloro-2-(5-methyl pyridin-3-yl)[1,2,4] triazolo[1,5-a]pyridine 245.6

Example 44

Step A. 5-bromo-N-(5-methylpyridin-2-yl)nicotinimidamide

n-Butyllithium (1.6 M, 5.14 mL, 0.0081 mol) was added slowly at atemperature of −78° C. over a period of 5 min to a solution of5-methylpyridin-2-amine (0.738 g, 0.0068 mol) in anhydroustetrahydrofuran (40 mL). The reaction temperature was raised to −40° C.and the reaction mixture was stirred for 15 min. It was cooled to −78°C. and 5-bromonicotinonitrile (1.25 g, 0.0068 mol) in tetrahydrofuran (5mL) was added. The reaction temperature was raised to RT and thereaction mixture was stirred for 3 h. The reaction mixture was quenchedwith a saturated aqueous ammonium chloride solution (25 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers weredried over sodium sulphate and concentrated under vacuum to afford thecrude product, which was used directly on the next step. MS (M+1):292.1.

Step B. 2-(5-bromopyridin-3-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine

Lead tetra acetate (2.28 g, 0.0051 mol) was added to a solution of5-bromo-N-(5-methylpyridin-2-yl)nicotinimidamide (44-1; 1 g, crude0.0034 mol) in toluene (40 mL) in a 80 mL microwave vial at RT. Thereaction mixture was heated to 150° C. for 2.5 h under microwaveirradiation. It was concentrated under vacuum to afford the crudeproduct, which was purified by silica gel column chromatography toafford the title compound. MS (M+1): 290.1

Step C.2-(5-cyclopropylpyridin-3-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine

Cesium carbonate (0.45 g, 0.0013 mol) was added to a stirred solution of2-(5-bromopyridin-3-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (44-2;0.2 g, 0.00069 mol) and cyclopropylboronic acid (0.119 g, 0.00138 mol)in a mixture of 1,4-dioxan (9 mL) and water (3 mL). The reaction mixturewas purged with argon for 20 min. Pd(dppf)₂Cl₂.DCM (0.028 g, 0.000034mol) was added and the reaction flask was again purged with argon for 10min. The reaction mixture was then stirred at 100° C. for 18 h. Thereaction mixture was filtered through a filter bed of CELITE and thefilter bed was thoroughly washed with ethyl acetate (2×50 mL). Thecollected organic factions were concentrated under vacuum to afford thecrude product, which was purified by silica gel column chromatography toafford the title compound. ¹H NMR (400 MHz, DMSO) δ 9.08-9.07 (d, J=1.2Hz, 1H), 8.83 (s, 1H), 8.50-8.49 (d, J=2.4 Hz, 1H), 8.04 (s, 1H),7.78-7.76 (d, J=8.8 Hz, 1H), 7.57-7.55 (d, J=9.2 Hz, 1H), 2.37 (s, 3H),2.08-2.05 (m, 1H), 1.08-1.03 (m, 2H), 0.84-0.80 (m, 2H)., MS (M+1):251.2.

The compounds in Table 8 were prepared using the chemistry described inExample 44.

TABLE 8 LCMS Ex Structure IUPAC Name (M + 1) 45

6-methyl-2-(5-methyl yridin-3-yl)[1,2,4] triazolo[1,5-a]pyridine 225.246

2-(5-ethylpyridin-3- yl)-6-methyl[1,2,4] triazolo[1,5-a]pyridine 239.2

Example 47

Step A. N-(4-fluoropyridin-2-yl)-2,2-dimethylpropanamide

To a solution of 4-fluoropyridin-2-amine (1 g, 0.0089 mol) in pyridine(3.87 mL) pivaloyl chloride (1.64 mL, 0.0133 mol) was added. Thereaction mixture was allowed to stir at RT for 5 h. and was then dilutedwith water (25 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were dried over sodium sulphate and concentratedunder vacuum to afford the crude product, which was purified by silicagel column chromatography to afford the title compound. ¹H NMR (400 MHz,DMSO) δ 10.07 (s, 1H), 8.35-8.32 (m, 1H), 7.90-7.87 (d, J=12 Hz, 1H),7.04-7.00 (m, 1H), 1.22 (s, 9H) MS (M+1): 197.1.

Step B. N-(4,5-difluoropyridin-2-yl)-2,2-dimethylpropanamide

N-(4,5-difluoropyridin-2-yl)-2,2-dimethylpropanamide was added slowlysolution of N-(4-fluoropyridin-2-yl)-2,2-dimethylpropanamide (47-1; 0.4g, 0.0020 mol) in anhydrous tetrahydrofuran (20 mL) at −78° C. over 30min. Then N-fluoro benzenesulphonimide in tetrahydrofuran (5 mL) wasadded slowly and stirred for 20 min. The reaction mixture was warmed toRT and quenched with a saturated aqueous ammonium chloride solution (25mL) and then extracted with ethyl acetate (2×50 mL). The combinedorganic layers were dried over sodium sulphate and concentrated undervacuum to afford the crude product, which was purified by silica gelcolumn chromatography to afford the title compound. MS (M+1): 215.1.

Step C. 4,5-difluoropyridin-2-amine

N-(4,5-difluoropyridin-2-yl)-2,2-dimethylpropanamide (47-2; 0.380 g) inconcentrated HCl was heated at 95° C. for 5 h. The reaction mixture wascooled to RT, diluted with ice cold water (20 mL) and basified with 10%aqueous sodium hydroxide solution. The reaction mixture was extractedwith ethyl acetate (2×50 mL). The combined organic layers were driedover sodium sulphate and concentrated under vacuum to afford the titlecompound. ¹H NMR (400 MHz, DMSO) δ 7.72-7.67 (m, 1H), 6.59-6.55 (m, 1H),6.48 (bs, 2H).

Step D.1,2-diamino-4,5-difluoropyridinium-2,4,6-trimethylbenzenesulfonate

2-[(Aminooxy)sulfonyl]-1,3,5-trimethylbenzene was added to a solution of4,5-difluoropyridin-2-amine (47-3; 0.1 g, 0.000769 mol) indichloromethane (10 mL). The reaction mixture was stirred for 20 min. Aprecipitate formed and it was filtered and dried under vacuum to affordthe title compound. ¹H NMR (400 MHz, DMSO) δ 8.91 (bs, 2H), 8.07-8.04(m, 1H), 7.11-7.05 (m, 1H), 6.87 (s, 2H), 6.71 (s, 2H), 2.47 (s, 6H),2.15 (s, 3H).

Step E.6,7-difluoro-2-[4-(trifluoromethyl)pyridin-3-yl][1,2,4]triazolo[1,5-a]pyridine

4-(trifluoromethyl)nicotinaldehyde was added to a solution of1,2-diamino-4,5-difluoropyridinium 2,4,6-trimethylbenzenesulfonate(47-4; 0.2 g, 0.000579 mol) in ethanol (20 mL) while stirring, followedby the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reactionmixture was stirred for 12 h at RT. It was then concentrated undervacuum, diluted with water (50 mL) and extracted with ethyl acetate(2×50 mL). The collected organic parts were concentrated under vacuum toafford the crude product, which was purified by silica gel columnchromatography to afford the title compounds. ¹H NMR (400 MHz, DMSO) δ8.20 (s, 1H), 9.09-9.06 (m, 1H), 9.03-9.02 (d, J=4 Hz, 1H), 7.99-7.77(d, J=8 Hz, 1H), 7.61-7.55 (m, 1H). HPLC purity—99.13%, MS (M+1): 301.1.

Example 48 was synthesized following the synthetic procedure asdescribed above for Example 47.

TABLE 9 LCMS Ex Structure IUPAC Name (M + 1) 48

2-(4-ethyl-5- fluoropyridin-3- yl)-6,7-difluoro[1,2,4]triazolo[1,5-a]pyridine 279.2

Assay Description and Results

Methods for V79-Human-CYP11B2 and V79-Human-CYP11B1 Assays:

V79 cell lines stably expressing the either the human CYP11B2 or thehuman CYP11B1 enzyme were generated using a standard transfectionprotocol. V79 cells were transfected with plasmidspTriEx3-Hygro-hCyp11B2 or pTriEx3-Hygro-hCyp11B1 using Lipofectamine2000reagent. V79 cells that stably express the human CYP11B2 or humanCYP11B1 enzyme were selected for and maintained in DMEM supplementedwith 10% FBS and 400 g/mL hygromycin for ˜2 weeks. Single cell cloneswere generated by infinite dilution in DMEM supplemented with 10% FBSand 400 g/mL hygromycin until single colonies were obtained. ClonesV79-hCYP11B2-CLE9 and V79-hCYP11B1-8CL7, were determined to produce themost aldosterone and cortisol, respectively, and were selected forinhibitor screening. For testing of inhibitors, cells were harvested at80% confluency with 0.05% Trypsan-EDTA, washed once in PBS, andreconstituted in DMEM+0.1% BSA media at a cell concentration of 600,000cells/mL for the CYP11B2 assay and 280,000 cells/ml for the CYP11B1assay. 25 μL of cells were added to a 384 well tissue culture treatedplate and mixed with 0.3 μL of inhibitor or DMSO (1% final DMSOconcentration) for 1 hour at 37° C., 5% CO₂. After pre-incubation withinhibitor, the reaction was initiated by adding 5 μL of substrate (finalconcentration of 125 nM 11-deoxycorticosterone for the CYP11B2 assay or250 nM 11-deoxycortisol for the CYP11B1 assay). The reaction was carriedout for 3 hours at 37° C., 5% CO₂ and was stopped by harvesting thesupernatants. The amount of product in the supernatant (aldosterone forCYP11B2 assay and cortisol for the CYP11B1 assay) was measured usingHTRF-based assay kit (Aldosterone HTRF-CisBio #64ALDPEB, CortisolHTRF-CisBio #63IDC002-CORT). IC₅₀s for the inhibitor were determined byplotting the amount of product formed against the concentration ofinhibitor using sigmoidal dose-response curve (variable slope) fit inGraphPad.

The compounds of Examples 1-21 were tested in the V79-Human-CYP11B2 cellassay and found to have IC₅₀s for inhibition of human CYP11B2 of lessthan 10000 nM. A sub-group of compounds had IC₅₀s less than or equal to250 nM, and a further sub-group of compounds had IC₅₀s less than orequal to 50 nM.

The compounds of Examples 1-21 were also tested in the V79-Human-CYP11B1cell assay. A sub-group of compounds were at least 10-fold moreselective for inhibition of CYP11B2 as compared to CYP11B1, and afurther sub-group of compounds were at least 30-fold more selective forinhibition of CYP11B2. Representative examples of data collected forcompounds of the present invention are shown in Table 10 below

TABLE 10 V79 Human V79 Human CYP11B2 CYP11B1 Example IUPAC Name IC₅₀(nM) IC₅₀ (nM) 5 4-([1,2,4]triazolo[1,5-a]pyridin-2- 138 >8333yl)isoquinoline 7 4-(8-chloro-[1,2,4] triazolo[1,5- 171 >8333a]pyridin-2-yl)isoquinoline 12 2-(5-(6-fluoro-[1,2,4] triazolo[1,5-1067 >8333 a]pyridin-2-yl)pyridin-3-yl)propan-2-ol 132-(5-bromopyridin-3-yl)-5-methyl- 884 >8333 [1,2,4]triazolo[1,5-a]pyridin 18 4-(6,8-difluoro-[1,2,4] triazolo[1,5-126 >8333 a]pyridin-2-yl)isoquinoline 20 4-(7-fluoro-[1,2,4]triazolo[1,5- 22 1076 a]pyridin-2-yl)isoquinoline 21 4-(6-fluoro-[1,2,4]triazolo[1,5- 46 2151 a]pyridin-2-yl)isoquinoline

While the invention has been described with reference to certainparticular embodiments thereof, numerous alternative embodiments will beapparent to those skilled in the art from the teachings describedherein. Recitation or depiction of a specific compound in the claims(i.e., a species) without a specific stereoconfiguration designation, orwith such a designation for less than all chiral centers, is intended toencompass the racemate, racemic mixtures, each individual enantiomer, adiastereoisomeric mixture and each individual diastereomer of thecompound where such forms are possible due to the presence of one ormore asymmetric centers. All patents, patent applications andpublications cited herein are incorporated by reference in theirentirety.

1. A compound of the structural formula

or a pharmaceutically acceptable salt thereof wherein: Ring A isattached to Ring B via positions D and E and is:

Ring B is a heteroaromatic ring; D is C; E is N; R¹ is H or alkyl; R² isaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁴ is H;halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)R⁷; —C(O)R⁷; —C(O)N(R⁸R⁹);—C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—R⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)S(O)₂—R⁷or —S(O)_(n)R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted oneor more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁵ is H; halogen; —CN; —OR⁷; —NR⁸R⁹;—N(R¹⁰)C(O)R⁷; —C(O)N(R⁸)(R⁹), —C(O)R⁷; —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷;—N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—R⁷; alkyl optionally substituted one or moretimes by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)S(O)₂—R⁷ or —S(O)_(n)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or R⁴ and R⁵ are joinedtogether to form a 5-7 membered carbocyclic or heterocyclic ring that isfused to the pyridyl ring to which R⁴ and R⁵ are attached, wherein thering formed by R⁴ and R⁵ is optionally substituted by 1 to 3 R⁶; R⁶ isindependently H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)R⁷;—C(O)N(R⁷)(R⁸); —C(O)N(R⁸)(R⁹); —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)SO₂—R⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted oneor more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁷ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR¹⁰, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OH, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰ or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R⁹)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; R⁸ is independently H or alkyl; R⁹ is independently H oralkyl; or R⁸ and R⁹ are joined together with the nitrogen to which theyare attached form a saturated 5- to 7-membered heterocyclic ring; R¹⁰ isindependently H or alkyl; R¹¹ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; R¹² is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; a is 0, 1, 2, 3 or 4; n is 1 or 2; and m is 0,1 or
 2. 2. The compound as defined in claim 1 or a pharmaceuticallyacceptable salt thereof, which has the structural formula Formula II

wherein: R² is phenyl optionally substituted by halogen; R⁴ is H,halogen, —CN, alkyl, haloalkyl or cycloalkyl; R⁵ is: i.) H, halogen,—CN, alkyl, —OR⁷, haloalkyl or phenyl optionally substituted by halogen,haloalkyl, cycloalkyl or —OR⁷; or ii.) a group of the formula:

where: R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to3 —F; R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1 to3 —F; R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3 —F;—OC₁—C₃-alkyl; —N(H)S(O)₂—C₁-C₃-alkyl; optionally substituted with 1 to3 —F; or —N(H)C(O)C₁-C₃-alkyl, optionally substituted with 1 to 3 —F; R⁷is independently H, alkyl, haloalkyl, or phenyl optionally substitutedby halogen; and a is 0, 1 or
 2. 3. (canceled)
 4. The compound as definedin claim 1 or a pharmaceutically acceptable salt thereof, which has thestructural formula

wherein: R² is phenyl optionally substituted by halogen; R⁶ is alkyl orhalo; R⁷ is H, alkyl, haloalkyl, cycloalkyl, or phenyl optionallysubstituted by halogen; a is 0, 1 or 2; and b is 0, 1 or
 2. 5.(canceled)
 6. The compound as defined in claim 1 which is:8-phenyl-2-(pyridine-3-yl-[1,2,4]triazolo[1,5-a]pyridine or apharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula I as defined in claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 8. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of Formula I as defined in claim 1 or apharmaceutically acceptable salt thereof, a therapeutically effectiveamount of at least one additional therapeutic agent and apharmaceutically acceptable carrier.
 9. A method for the treatment,amelioration or prevention of one or more conditions associated withinhibiting CYP11B2, which comprises administering a therapeuticallyeffective amount at least one compound of Formula I as defined in claim1 or a pharmaceutically acceptable salt thereof to a mammal in need ofsuch treatment.
 10. The method according to claim 9 wherein theconditions are hypertension, heart failure such as congestive heartfailure, diastolic dysfunction, left ventricular diastolic dysfunction,heart failure, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, systolic dysfunction, hypokalemia,renal failure, restenosis, syndrome X, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,vascular diseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, ischemia, myocardial andvascular fibrosis, myocardial necrotic lesions, vascular damage,myocardial necrotic lesions, myocardial infarction, left ventricularhypertrophy, cardiac lesions, vascular wall hypertrophy, endothelialthickening or fibrinoid necrosis of coronary arteries.
 11. A method forinhibiting CYP11B2 in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound of theformula

or a pharmaceutically acceptable salt thereof wherein: Ring A isattached to Ring B via positions D and E and is:

Ring B is a heteroaromatic ring; D is C; E is N; R¹ is H or alkyl; R² isaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁴ is H;halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)R⁷; —C(O)R⁷; —C(O)N(R⁸)(R⁹);—C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—R⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)S(O)₂—R⁷or —S(O)_(n)R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted oneor more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁵ is H; halogen; —CN; —OR⁷; —NR⁸R⁹;—N(R¹⁰)C(O)R⁷; —C(O)N(R⁸)(R⁹); —C(O)R⁷; —C(O)OR⁷; —SO₂N(R)—R⁷;—N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—R⁷; alkyl optionally substituted one or moretimes by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R¹⁰)—R⁷, —N(R¹⁰)S(O)₂—R⁷, or —S(O)_(n)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or R⁴ and R⁵ are joinedtogether to form a 5-7 membered carbocyclic or heterocyclic ring that isfused to the pyridyl ring to which R⁴ and R⁵ are attached, wherein thering formed by R⁴ and R⁵ is optionally substituted by 1 to 3 R⁶; R⁶ isindependently H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)R⁷;—C(O)N(R⁷)(R⁸); —C(O)N(R⁸)(R⁹); —C(O)OR⁷; —SO₂N(R¹⁰)—R⁷; —N(R¹⁰)SO₂—R⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R¹⁰)—R⁷, —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted oneor more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R¹⁰)—R⁷,—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁷ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR¹⁰, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OH, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰ or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R⁹)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; R⁸ is independently H or alkyl; R⁹ is independently H oralkyl; or R⁸ and R⁹ are joined together with the nitrogen to which theyare attached form a saturated 5- to 7-membered heterocyclic ring; R¹⁰ isindependently H or alkyl; R¹¹ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; R¹² is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; a is 0, 1, 2, 3 or 4; n is 1 or 2; and m is 0,1 or 2.